Clonal anergy is now recognized as an important mechanism by which the immune system can induce T-cell tolerance to peripheral self-antigens. Previous studies of murine helper T-cell clones in vitro have led to the paradigm of proliferative clonal anergy, and suggest that T cells induced into anergy loose the capacity to proliferate in response to antigen stimulation. The model predicts that such an inability to proliferate would severely limit the ability of a low-frequency population of autoreactive T-cells to initiate a pathological effector response. Recent experiments using ThO T-cell clones have established, however, that proliferative clonal anergy in vitro is not the result of a global T-cell inactivation. Rather, anergic ThO cells exhibit profound transcriptional inhibition of only selected lymphokine genes. In particular, expression of the IL-2 gene is blocked, whereas production of the growth and differentiation factor IL-4 can still occur. While it remains uncertain whether this differential inhibition of T-cell activation genes is the result of a proximal signaling defect or inhibition by gene-specific nuclear factors, it is now clear that certain activation events do take place following the stimulation of anergic T cells. These data suggest that an already expanded T-cell population, even if induced into clonal anergy, would still be capable of initiating some form of an immune response. We now hypothesize that the induction of clonal anergy in a T-cell population is associated with the development of a Th2-like effector-cell phenotype. Such anergic T cells would fail to mediate a DTH response, but could provide B-cell helper signals. The experiments proposed here will test this hypothesis by 1) characterizing the expression of lymphokine gene and activation antigens in anergic ThO T cells, 2) determining the functional capacity of anergic ThO T cells to induce the growth and differentiation of B cells, and to mediate a delayed-type hypersensitivity response, and 3) by examining the capacity of TCR-transgenic T cells from tolerant animals to transfer a DTH response and provide help for antibody production in vivo. Taken together, these experiments will establish the functional capacity of anergic T cells and help determine the potential role of clonal anergy in shaping the phenotype of a T-cell immune response. The information gained in the study will also contribute to our understanding of the fundamental biological principles responsible for the control of T-cell responsiveness by clonal anergy. Finally, the results may be of particular importance to those therapies designed to establish transplantation tolerance, and to treat autoimmune disease through the induction of clonal anergy in the putative self-antigen specific T-cell population.